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US9101620B2 - Polymorph of 3-(substituteddihydroisoindolinone-2-yl)-2,6-dioxopiperidine, and pharmaceutical compositions thereof - Google Patents

Polymorph of 3-(substituteddihydroisoindolinone-2-yl)-2,6-dioxopiperidine, and pharmaceutical compositions thereof Download PDF

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US9101620B2
US9101620B2 US13/501,437 US201013501437A US9101620B2 US 9101620 B2 US9101620 B2 US 9101620B2 US 201013501437 A US201013501437 A US 201013501437A US 9101620 B2 US9101620 B2 US 9101620B2
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piperidine
dihydro
oxo
dione
amino
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Rong Yan
Hao Yang
Yongxiang Xu
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Nanjing Cavendish Bio Engineering Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention is in the field of polymorph of pharmaceutical compounds, and more specifically it relates to polymorph of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione, and as well the preparing methods and pharmaceutical compositions thereof.
  • 3-(substituted dihydroisoindolinone-2-yl)-2,6-dioxopiperidine in particular 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione was disclosed in the article “Amino-substituted thalidomide analogs: Potent inhibitors of TNF- ⁇ production” (Muller etc., Bioorganic & Medicinal Chemistry Letters, Vol. 9, Issue 11, 7 Jun., 1999: pp 1625-1630) and Chinese Patent ZL97180299.8.
  • the diseases and syndromes which can be treated by 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione include, but are not limited to: myeloproliferative disorder, myelodysplasia syndrome, vasculogenesis, cancer, pain, macular degeneration, asbestosis, anaemia, nervous system disease, dyssomnia, dermatosis, pulmonary hypertension, immune deficiency disorder, parasitic diseases, central lesion etc., namely that were described in the following Chinese Patents with the application numbers, which are incorporated herein in their entirety by reference: 97180299.8, 98805614.3, 03825761.0, 03825567.7, 03813733.X, 03816899.5, 200610150484.3, 200380107531.0, 200710103924.4, 200380108093.X, 200380108398.0, 200480043341.1, 200480038171.8, 20048003555
  • 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione is practically insoluble in water or organic solvent (e.g. hexane, toluene, acetone, acetonitrile, methanol, ethyl acetate etc.), even in the condition of heating, a large amount (over 100 times) of solvent is needed, which is disadvantageous in industrial production; in addition, with the method described in the Patent CN 1871003A, the appearance, color and luster of the products can not be improved from light yellow to white or off-white; also, it was not taken into consideration that harmful organic solvent sorted in or above class II (e.g. toluene and acetonitrile etc.) should be tried not to use in synthesis of final products to minimize the negative effects of the residual organic solvent in products on human body.
  • organic solvent e.g. hexane, toluen
  • each polymorph has different chemical and physical characteristics, including melting point, chemical stability, apparent solubility, rate of dissolution, optical and mechanical properties, vapor pressure as well as density. Such characteristics can directly influence the work-up or manufacture of bulk drug and formulation, and also affect the stability, solubility and bioavailability of formulation. Consequently, polymorph of drug is of great importance to quality, safety and efficacy of pharmaceutical preparation.
  • 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione there are still needs in the art for new polymorphs suitable for industrial production and with excellent physical and chemical properties as well.
  • the inventors of this invention have experienced a large amount of researches and unexpectedly found new polymorphs of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione to overcome the deficiencies of the prior art, and the new polymorphic forms have excellent physical and chemical properties and good stabilities, which are suitable for industrial production.
  • a purpose of this invention is to provide new polymorphs of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione.
  • Another purpose of this invention is to provide the synthetic methods of these new polymorphs mentioned above.
  • the third purpose of this invention is to provide pharmaceutical compositions comprising the mentioned new polymorphs.
  • FIG. 1 is an XRPD pattern of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 2 is an IR diagram of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 3-1 and FIG. 3-2 are respectively DSC diagram and TGA diagram of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 4 is a 13C MAS NMR spectrum of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 5 is an XRPD pattern of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after strong illumination for 10 days.
  • FIG. 6 is a DSC diagram of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after strong illumination for 10 days.
  • FIG. 7 is an XRPD pattern of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high temperature test of 60° C. for 10 days.
  • FIG. 8 is a DSC diagram of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high temperature test of 60° C. for 10 days.
  • FIG. 9 is an XRPD pattern of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high humidity for 10 days.
  • FIG. 10-1 and FIG. 10-2 are respectively DSC diagram and TGA diagram of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high humidity for 10 days.
  • FIG. 11 is an XRPD pattern of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after accelerated test at 40° C. for six months.
  • FIG. 12-1 and FIG. 12-2 are respectively DSC diagram and TGA diagram of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after accelerated test at 40° C. for six months.
  • FIG. 13 is an XRPD pattern of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 14 is an IR diagram of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 15-1 and FIG. 15-2 are respectively DSC diagram and TGA diagram of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 16 is an XRPD pattern of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after strong illumination for 10 days.
  • FIG. 17 is a DSC diagram of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after strong illumination for 10 days.
  • FIG. 18 is an XRPD pattern of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high temperature test of 60° C. for 10 days.
  • FIG. 19 is a DSC diagram of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high temperature test of 60° C. for 10 days.
  • FIG. 20 is an XRPD pattern of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high humidity for 10 days.
  • FIG. 21-1 and FIG. 21-2 are respectively DSC diagram and TGA diagram of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high humidity for 10 days.
  • FIG. 22 is an XRPD pattern of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after accelerated test at 40° C. for six months.
  • FIG. 23-1 and FIG. 23-2 are respectively DSC diagram and TGA diagram of the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after accelerated test at 40° C. for six months.
  • FIG. 24 is an XRPD pattern of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 25 is an IR diagram of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 26-1 and FIG. 26-2 are respectively DSC diagram and TGA diagram of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • FIG. 27 is XRPD pattern of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after strong illumination for 10 days.
  • FIG. 28 is DSC diagram of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after strong illumination for 10 days.
  • FIG. 29 is an XRPD pattern of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high temperature test of 60° C. for 10 days.
  • FIG. 30 is a DSC diagram of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high temperature test of 60° C. for 10 days.
  • FIG. 31 is an XRPD pattern of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high humidity for 10 days.
  • FIG. 32-1 and FIG. 32-2 are respectively DSC diagram and TGA diagram of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after high humidity for 10 days.
  • FIG. 33 is an XRPD pattern of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after accelerated test at 40° C. for six months.
  • FIG. 34-1 and FIG. 34-2 are respectively DSC diagram and TGA diagram of the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention after accelerated test at 40° C. for six months.
  • FIG. 35 is a comparative IR spectrum of the Polymorph I, II and III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention.
  • this invention provides a Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione with a half-molecule water and substantially without other solvents.
  • the invention provides a Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione hemihydrate having the X-ray powder diffraction pattern by using Cu—Ka radiation, characterized by diffraction peaks at 11.9 ⁇ 0.2 and 22.0 ⁇ 0.2 of 2 ⁇ indicated with degree, further, one or multiple (in optional combination, including two or more peaks, or all peaks) of diffraction peaks at 15.6 ⁇ 0.2, 22.5 ⁇ 0.2, 23.8 ⁇ 0.2, 26.4 ⁇ 0.2, 27.5 ⁇ 0.2 and 29.1 ⁇ 0.2; as is shown in FIG. 1 .
  • Peak Flex Number 2 ⁇ Width d-Value Intensity L/LO 1 11.940 0.212 7.4060 17891 84 2 13.020 0.235 6.7940 5996 28 3 13.780 0.188 6.4210 6550 31 6 15.620 0.235 5.6685 9017 42 9 17.960 0.259 4.9349 5895 28 10 19.080 0.235 4.6476 8374 39 11 19.480 0.235 4.5531 6273 30 12 20.580 0.235 4.3121 6162 29 15 21.980 0.235 4.0405 21530 100 16 22.520 0.259 3.9449 13747 64 18 23.760 0.259 3.7417 15053 70 19 24.400 0.212 3.6450 5016 24 21 26.440 0.282 3.3682 15819 74 22 27.520 0.353 3.2384 11455 54 23 29.060 0.306 3.0702 11190 52 24 30.980 0.306 2.8842 6238 29 25 32.000 0.376 2.7945 4934 23 26 33.040 0.306 2.7089 53
  • the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione hemihydrate provided by this invention is characterized in that its DSC (differential scanning calorimetry) has the first endothermic peak between 140° C. and 180° C., more specifically, at about 164.87° C., and the second endothermic peak, namely the maximal endothermic transformation, at about 268.86° C.
  • DSC diagram of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione hemihydrate of this invention is as in FIG. 3-1
  • TGA (Thermal Gravimetric Analysis) diagram is as in FIG. 3-2 .
  • the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione hemihydrate in this invention has IR (Infrared Spectrum) in KBr disc, which is characterized by absorption peaks at about 3561.4 cm ⁇ 1 , 3507.4 cm ⁇ 1 , 3424.2 cm ⁇ 1 , 3345.8 cm ⁇ 1 , 3091.0 cm ⁇ 1 , 2912.5 cm ⁇ 1 , 1697.8 cm ⁇ 1 , 1658.8 cm ⁇ 1 , 1610.0 cm ⁇ 1 , 1494.3 cm ⁇ 1 , 1349.5 cm ⁇ 1 , 1201.4 cm ⁇ 1 ; as in FIG. 2 .
  • the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione hemihydrate in this invention has characteristic chemical shifts ⁇ (ppm) in 13 C solid-state NMR spectrum: 22.25 ppm, 30.18 ppm, 43.63 ppm, 45.98 ppm, 50.45 ppm, 110.19 ppm, 111.24 ppm, 114.25 ppm, 115.06 ppm, 117.25 ppm, 118.18 ppm, 124.22 ppm, 125.20 ppm, 125.91 ppm, 126.88 ppm, 128.87 ppm, 129.93 ppm, 132.96 ppm, 133.88 ppm, 140.62 ppm, 143.27 ppm, 168.67 ppm, 170.13 ppm,
  • this invention provides a preparing method of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione hemihydrates, including the following steps:
  • this invention provides a solvated Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione having the X-ray powder diffraction pattern by using Cu—Ka radiation, characterized by diffraction peaks at 15.7 ⁇ 0.2 and 25.2 ⁇ 0.2 of 2 ⁇ indicated with degree, further, one or multiple (in optional combination, including two or more peaks, or all peaks) of diffraction peaks at 7.8 ⁇ 0.2, 8.6 ⁇ 0.2, 14.2 ⁇ 0.2, 17.1 ⁇ 0.2, 17.9 ⁇ 0.2, 18.8 ⁇ 0.2, 21.4 ⁇ 0.2, 21.9 ⁇ 0.2, 22.6 ⁇ 0.2, 23.4 ⁇ 0.2, 24.2 ⁇ 0.2, 27.1 ⁇ 0.2 and 29.3 ⁇ 0.2; as is shown in FIG. 13
  • the (acetonitrile) solvated Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione provided by this invention is characterized in that its DSC has the first endothermic peak between 140° C. and 170° C., more specifically, at about 152.73° C., and the second endothermic peak, namely the maximal endothermic transformation, at about 269.12° C.
  • DSC diagram of the (acetonitrile) solvated Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention is as in FIG. 15-1
  • TGA diagram is as in FIG. 15-2 .
  • the (acetonitrile) solvated Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione provided by this invention has IR in KBr disc, which is characterized by absorption peaks at about 3466.9 cm ⁇ 1 , 3366.5 cm ⁇ 1 , 3223.8 cm ⁇ 1 , 3078.0 cm ⁇ 1 , 2957.2 cm ⁇ 1 , 2871.0 cm ⁇ 1 , 1687.2 cm ⁇ 1 , 1666.7 cm ⁇ 1 , 1346.5 cm ⁇ 1 and 1199.1 cm ⁇ 1 ; as in FIG. 14 .
  • this invention provides preparing method of the (acetonitrile) solvated Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione, including the following steps:
  • this invention provides a solvated polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione having X-ray powder diffraction pattern by using Cu—Ka radiation, characterized by diffraction peaks at 17.4 ⁇ 0.2 and 24.5 ⁇ 0.2 of 2 ⁇ indicated with degree, further, one or multiple (in optional combination, including two or more peaks, or all peaks) of diffraction peaks at 14.5 ⁇ 0.2, 15.5 ⁇ 0.2, 18.7 ⁇ 0.2, 21.0 ⁇ 0.2, 21.9 ⁇ 0.2, 22.1 ⁇ 0.2, 24.0 ⁇ 0.2, 25.3 ⁇ 0.2 and 27.8 ⁇ 0.2; as is shown in FIG. 24 .
  • the (acetone) solvated Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione provided by this invention is characterized in that its DSC has the first endothermic peak between 150° C. and 200° C., more specifically, at about 188.96° C., and the second endothermic peak, namely the maximal endothermic transform, at about 268.19° C.
  • DSC diagram of the (acetone) solvated Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of this invention is as in FIG. 26-1
  • TGA diagram is as in FIG. 26-2 .
  • the (acetone) solvated polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione provided by this invention has IR in KBr disc, which is characterized by absorption peaks at about 3466.7 cm ⁇ 1 , 3363.3 cm ⁇ 1 , 3228.2 cm ⁇ 1 , 3081.7 cm ⁇ 1 , 2958.5 cm ⁇ 1 , 2877.2 cm ⁇ 1 , 1688.5 cm ⁇ 1 , 1666.2 cm ⁇ 1 , 1609.1 cm ⁇ 1 , 1491.7 cm ⁇ 1 , 1347.3 cm ⁇ 1 and 1199.5 cm ⁇ 1 ; as in FIG. 25 .
  • this invention provided a preparing method of the (acetone) solvated Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione, which including the following steps:
  • the scientific instruments and the test conditions involved in X-ray powder diffraction were: anode target-rotating X-ray diffractometer D/max-2500/PC-type (Japan Rigaku); Cu-target, graphite monochromator, tube voltage of 40 kV, tube current of 100 mA, both divergence slit and antidivergence slit of 1°, receiving slit of 0.3 mm, scanning speed of 5°/min and scanning range of from 3 to 40°.
  • the scientific instruments and the test conditions involved in DSC in this invention were: US Perkin Elmer Diamond DSC; heating from 25° C. to 300° C. at the rate of 10° C./min.
  • the scientific instruments and the test conditions involved in TGA in this invention were: US Perkin Elmer Thermal Analysis Pyris 1 TGA; heating from 25° C. to 300° C. at the rate of 10° C./min.
  • the scientific instruments and the test conditions involved in solid-state NMR in this invention were: instruments: wide-bore solid-state NMR spectrometer AVANCE III 400MH-type (BRUKER); test conditions: CP-MAS; methods: rotating speed of 14000 Hz, scanning times of 1404, relaxation delay of 40 s, contact time of 2 ms, 13 C frequency of 100.6234936 MHz and 1H frequency of 400.1413530 MHz.
  • test conditions and method of dissolution test were referred to Method 1 in Appendix XC of Chinese Pharmacopoeia Edition 2005.
  • the sample was added into 500 ml (for 5 mg strength) or 1000 ml (for 10 mg or 25 mg of strength) of water as medium, and stirred at 100 rounds per minute, then preceded the procedure in the Method 1. After 45 minutes, a quantity of the solution was filtered, and the first filtrate was discarded and the following filtrate was taken as test solution for study (for 5 mg or 10 mg of strength); 10 ml of the following filtrate was measured accurately to be sample solution for study (for 25 mg of strength).
  • UV-vis spectrophotometry Appendix IVA of Chinese Pharmacopoeia Edition 2005
  • absorbency of sample solution and standard solution were determined at 240 nm wavelength and the dissolving-out amount of per pill (or tablet) was calculated by absorbency on the basis of ESTD.
  • Test was performed according to the Examples of Chinese Pharmacopoeia Edition 2005.
  • Method a definite quantity of the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione (hemihydrate) measured accurately was added into a certain quantity of solvent slowly, while the mixture was shaken strongly for 30 seconds every 5 minutes and the dissolving status within 30 minutes was observed. Results were listed in Tab. 1.
  • the Polymorph 1 of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione (hemihydrate) was: freely soluble in dimethylsulfoxide; soluble in N,N-dimethylformamide and acetic acid; sparingly soluble in 0.1 mol/L NaOH solution; slightly soluble in 0.1 mol/L HCL solution, acetonitrile, methanol and acetone; very slightly soluble in water, ethanol and ethyl acetate.
  • the Polymorph I of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione (hemihydrate) was distributed homogeneously in open petri dish with the thickness of the raw material not more than 5 mm, and the distance was adjusted to make illumination intensity at 4500 ⁇ 500 Lx. Sample was tested at the 5 th and 10 th day respectively and the results were contrasted with that of the Day 0. Results were listed in Tab. 2. After strong illumination for 10 days, the X-ray powder diffraction pattern was shown in FIG.
  • the raw material of Polymorph 1 of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione (hemihydrate) was distributed homogeneously in open petri dish with thickness of the raw material not more than 5 mm and put into thermostatic and humidostatic incubator at room temperature (about 25° C.) and 75 ⁇ 5% relative humidity. Sample was tested at the 5 th and 10 th day respectively and the results were contrasted with that of the Day 0. Results were listed in Tab. 4. After high humidity test of 75 ⁇ 5% relative humidity for 10 days, the X-ray powder diffraction pattern was shown in FIG. 9 ; DSC diagram was in FIG. 10-1 ; TGA diagram was in FIG. 10-2 .
  • Test was performed according to the Examples of Chinese Pharmacopoeia Edition 2005.
  • Method a definite quantity of the (acetonitrile) solvated Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione measured accurately was added into a certain quantity of solvent slowly, while the mixture was shaken strongly for 30 seconds every 5 minutes and the dissolving status within 30 minutes was observed. Results were listed in Tab. 61.
  • the Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2h-isoindole-2-yl)-piperidine-2,6-dione was: freely soluble in dimethylsulfoxide and N,N-dimethylformamide; sparingly soluble in acetic acid and 0.1 mol/L HCL solution; slightly soluble in acetonitrile, acetone and 0.1 mol/L NaOH solution; very slightly soluble in methanol, ethanol and ethyl acetate; nearly insoluble in water.
  • the raw material of Polymorph II of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione was distributed homogeneously in open petri dish with thickness of the raw material not more than 5 mm and put into thermostatic and humidostatic incubator at room temperature (about 25° C.) and 75 ⁇ 5% relative humidity. Sample was tested at the 5 th and 10 th day respectively and the results were contrasted with that of the Day 0. Results were listed in Tab. 9. After high humidity test of 75 ⁇ 5% relative humidity for 10 days, the X-ray powder diffraction pattern was shown in FIG. 20 ; DSC diagram was in FIG. 21-1 ; TGA diagram was in FIG. 21-2 .
  • Test was performed according to the Examples of Chinese Pharmacopoeia Edition 2005.
  • Method a definite quantity of the (acetone) solvated polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione measured accurately was added into a certain quantity of solvent slowly while the mixture was shaken strongly for 30 seconds every 5 minutes and the dissolving status within 30 minutes was observed. Results were listed in Tab. 11.
  • the Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione was: soluble in dimethylsulfoxide and N,N-dimethylformamide; sparingly soluble in acetic acid and 0.1 mol/L NaOH solution; slightly soluble in 0.1 mol/L HCL solution, acetonitrile, methanol and acetone; very slightly soluble in water, ethanol and ethyl acetate.
  • the raw material of Polymorph III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione was distributed homogeneously in open petri dish with thickness of the raw material not more than 5 mm and put into thermostatic and humidostatic incubator at room temperature (about 25° C.) and 75 ⁇ 5% relative humidity. Sample was tested at the 5 th and 10 th day respectively and the results were contrasted with that of the Day 0. Results were listed in Tab. 14. After high humidity test of 75 ⁇ 5% relative humidity for 10 days, the X-ray powder diffraction pattern was shown in FIG. 31 ; DSC diagram was in FIG. 32-1 ; TGA diagram was in FIG. 32-2 .
  • compositions comprising one or more of the Polymorph I, II and III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione and a pharmaceutical excipient; preferably, the pharmaceutical composition contains 500 mg of the polymorph of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione; more preferably, it contains 5 mg, 10 mg, 15 mg or 25 mg of the polymorph of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione.
  • the pharmaceutical compositions of this invention could be prepared into all kinds of formulations and the proper pharmaceutical excipient could be selected.
  • the pharmaceutical compositions of this invention could be delivered through such administration routes: oral, parenteral (e.g. intramuscular, intraperitoneal, intravenous, intracerebroventricular, intracisternal and subcutaneous injection or infusion), inhalation spray, nasal, vaginal, rectal, sublingual or local delivery; preferably, it is oral solid formulations, such as tablets, granules or capsules.
  • compositions of this invention containing the polymorph of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione, could comprises other therapeutic components depending on the needs.
  • the pharmaceutical composition of this invention was administrated once or multiple times every day on the basis of daily dose, and the daily dose was about from 0.10 mg to 500 mg per day, more preferably from 1 mg to 250 mg per day. Alternatively, the pharmaceutical composition was administrated every two days on the dose of about from 0.10 mg to 150 mg per day or from 1 mg to 250 mg per day.
  • the diseases and syndromes which can be treated by 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione of the invention include, but not limited to: myeloproliferative disorder, osteomyelodysplasia syndrome, vasculogenesis, cancer, pain, macular degeneration, asbestosis, anaemia, nervous system disease, dyssomnia, dermatosis, pulmonary hypertension, immune deficiency disorder, parasitic diseases and central lesion etc., and the specific methods and doses could refer to Chinese Patents with the application numbers: 97180299.8, 98805614.3, 03825761.0, 03825567.7, 03813733.X, 03816899.5, 200610150484.3, 200380107531.0, 200710103924.4, 200380108093.X, 200380108398.0, 200480043341.1, 200480038171.8, 200480035556.9, 200480020
  • the technical advantages of this invention include: although eight polymorphs of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione and the preparation methods thereof has been reported in the patent documentation of CN 1871003A, the polymorphs of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione prepared by the methods of the Patent CN 1871003A was verified that the polymorph A and the polymorph B had poor chemical stability in 0.1 mol/L diluted HCl solution and in the oxidation destroy experiment, and also the crystal transformation method described in the patent was unsuitable for industrial production.
  • the preparation method was that: 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione was added into water or organic solvent (e.g. hexane, toluene, acetone, acetonitrile, methanol and ethyl acetate) where it is practically insoluble for, after dissolved by heating, crystal was precipitated when being cooled or crystal transformed when being stirred for long time in slurrying system of solid-liquid diphase.
  • organic solvent e.g. hexane, toluene, acetone, acetonitrile, methanol and ethyl acetate
  • this invention provided the methods suitable to industrially manufacturing polymorphs of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione, which overcame the problems in existing technique.
  • this invention was beneficial to dramatic improvement in products quality and suitable to industrial production.
  • Contrasts Index of raw material Items before transformation Index of Polymorph I Appearance Yellow crystal powder White to off-white crystal powder Related substance ⁇ 0.31% ⁇ 0.05% Heavy metal ⁇ 20 ppm, ⁇ 50 ppm ⁇ 10 ppm Water content 0.097% 3.613% Melting point 263.97° C. 268.86° C.
  • the product weighted 72 g and yield was 72%.
  • Contrasts Items Index of raw material Index of polymorph II Appearance Yellow crystal powder White to off-white crystal powder Related substance ⁇ 0.31% ⁇ 0.09% Heavy metal ⁇ 20 ppm, ⁇ 50 ppm ⁇ 10 ppm Weight loss before 0.097% 11.31% 180° C. by TGA Melting by DSC 263.97° C. 269.12° C.
  • the product weighted 86 g and yield was 86%.
  • Contrasts Items Index of raw material Index of polymorph III Appearance Yellow crystal powder White to off-white crystal powder Related substance ⁇ 0.31% ⁇ 0.09% Heavy metal ⁇ 20ppm, ⁇ 50ppm ⁇ 10 ppm Weight loss before 0.097% 12.663% 200° C. by TGA melting point by DSC 263.97° C. 268.19° C.
  • the manufacturing method of tablets containing the polymorph I or II or III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione or a mixture of the above-mentioned Polymorph I, II and III in any ratio was: the above-mentioned excipients were mixed homogeneously with the Polymorph I or II or III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione or a mixture of the above-mentioned Polymorph I, II and III in any ratio, and a proper amount of 10% PVP solution was added to form the damp mass, which was then granulated by screening. The moist granules were dried and size stabilized by screening, and then magnesium stearate and talcum powder were added to be homogeneous mixture, which was tableted at last.
  • the manufacturing method of capsules containing the Polymorph I or II or III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione or a mixture of the above-mentioned Polymorph I, II and III in any ratio was: the above-mentioned excipients were mixed homogeneously with the Polymorph I or II or III of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione or a mixture of the above-mentioned three polymorphs in any ratio and a proper amount of 10% PVP solution was added to form the moist granules, which were dried and size stabilized by screening.
  • magnesium stearate was added to be homogeneous mixture, which was capsuled.
  • the homogeneous mixture of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione and above-mentioned excipients was screened and capsuled directly.
  • Polymorph I The methods of destruction experiment of the Polymorph I of this invention (hereinafter referred to as “Polymorph I”) contrasting with the Polymorph A and B of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione prepared by the method in CN 1871003A (hereinafter referred to as “Polymorph A” and “polymorph B”) and results of stability are followed:
  • Acid destruction 50 mg of sample weighted accurately was added into measuring flask of 100 mL, and 10 mL 0.1 mol/L HCl solution was added. After standing at room temperature for 1 hour, an equal amount of 0.1 mol/L NaOH solution was added for neutralization. Then the mixture was diluted with mobile phase to scale and shook to be homogeneous, and determined by HPLC.
  • Oxidation destruction 50 mg of sample weighted accurately was added into measuring flask of 100 mL, and 10 mL 30% H 2 O 2 was added. After standing at room temperature for 2 hour, the mixture was diluted with mobile phase to scale and shook to be homogeneous, and determined by HPLC.
  • HPLC conditions and system applicability octadecylsilane bonded silica as the filler; 0.01 mol/L of potassium dihydrogen phosphate (adjusted to pH 3.5 by phosphoric acid)-methanol-acetonitrile (80:15:5) as the mobile phase; detection wavelength was 240 nm; the number of theoretical plates should be not less than 2000, calculated according to the peak of lenalidomide.
  • the resolution of the peak of 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindole-2-yl)-piperidine-2,6-dione from the peaks of adjacent impurities should meet requirements.
  • sample was dissolved in mobile phase to be the solution containing 0.5 mg per 1 mL. 20 ⁇ L of such solution was injected into liquid chromatograph and chromatogram was recorded until fourfold the retention time of major component peak. If there were impurities peaks in the chromatogram of sample solution, total impurities and sole impurity were calculated by normalization method on the basis of peak area.
  • Polymorph I of this invention had better stability whether in the acid condition or in the oxidating condition, indicating that Polymorph I was more suitable to be made into pharmaceuticals.

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CN101696205B (zh) 2009-11-02 2011-10-19 南京卡文迪许生物工程技术有限公司 3-(取代二氢异吲哚-2-基)-2,6-哌啶二酮多晶型物和药用组合物
CN104072476B (zh) * 2013-03-27 2018-08-21 江苏豪森药业集团有限公司 泊马度胺晶型及其制备方法和用途
CN104016966A (zh) * 2014-01-30 2014-09-03 上海创诺制药有限公司 3-(4-氨基-1,3-二氢-1-氧代-2h-异吲哚-2-基)-2,6-哌啶二酮新晶型及其制备方法

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JP2013509357A (ja) 2013-03-14
EP2496568A1 (fr) 2012-09-12
CN101696205A (zh) 2010-04-21
ES2634666T3 (es) 2017-09-28
US20120203005A1 (en) 2012-08-09
WO2011050590A1 (fr) 2011-05-05
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AU2010312224A1 (en) 2012-04-12
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